Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 2D6 may increase plasma concentrations of pitolisant. The proposed mechanism is decreased clearance of pitolisant due to inhibition of its metabolism via this isoenzyme. Coadministration with the strong CYP450 2D6 inhibitor paroxetine was reported to increase the mean peak plasma concentration (Cmax) of pitolisant by approximately 47% and result in a 2-fold increase in its systemic exposure. No data are available for other, less potent CYP450 2D6 inhibitors. Clinically, high plasma levels of pitolisant may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution and clinical monitoring are recommended if pitolisant is used in combination with CYP450 2D6 inhibitors. Patients should be monitored for clinical response and increased adverse effects such as headache, insomnia, nausea, anxiety, increased heart rate, QT prolongation, hallucinations, abdominal pain, upper respiratory tract infections and musculoskeletal pain, and the dosage of pitolisant adjusted as necessary in accordance with the product labeling. A prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant can increase plasma concentrations and the risk of adverse effects of pitolisant for at least 28 days after administration of rolapitant.

The consumption of grapefruit juice may be associated with increased plasma concentrations of darifenacin. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The clinical significance is unknown.